Identification of Potential Therapeutic Target Genes for Bipolar Disorder through Systematic Druggable Genome-wide...

Bipolar Disorder (BD) is a severe psychiatric condition with high heritability and clinical heterogeneity. Despite numerous genetic variants linked to BD through Genome- Wide Association Studies (GWAS), the molecular mechanisms and effective therapeutic targets remain unclear. This study aims to identify potential therapeutic targets for BD using a systematic approach.

In this study, we performed a systematic druggable genome-wide Mendelian Randomization (MR) analysis to identify potential therapeutic target genes for BD. We integrated large-scale GWAS data, expression Quantitative Trait Loci (eQTL) datasets, and druggable gene resources to construct a set of 6,888 potential druggable genes. MR methods were applied to infer causal relationships between these genes and BD. Additionally, Protein-Protein Interaction (PPI) network analysis, Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to explore the biological functions and pathways involved. Drug enrichment analysis was performed to assess the association between identified genes and approved psychiatric drugs, while Bayesian colocalization analysis was used to provide evidence for causal genetic signals underlying potential druggable targets.

Our MR analysis revealed 34 genes with significant causal associations with BD. These genes were found to be predominantly involved in immune regulation, neuro-metabolic processes, and oxidative stress-related pathways. Drug enrichment analysis identified a close association between these genes and several approved psychiatric drugs, including trifluoperazine, clozapine, and alprazolam. Further, Bayesian colocalization analysis provided strong evidence for GSTM1 and CD52 as potential druggable targets for BD, suggesting that their gene expression shares causal genetic signals with disease susceptibility.

Our findings support previous studies linking immune dysregulation to BD, with the identified genes enriched in immune-metabolic and oxidative stress pathways. A key limitation is the reliance on GWAS data primarily from European cohorts, which may limit the generalizability to other populations.

This study prioritizes candidate druggable genes for BD through integrative analysis of GWAS, eQTL, MR, drug enrichment, and colocalization evidence. Our findings provide insights into BD-related molecular mechanisms and suggest potential avenues for target prioritization and drug repurposing research.